ATAD2 as a Cancer Target
Cancer is a group of different diseases which are commonly characterized by evolution of uncontrolled and abnormally proliferating cells which ultimately lead to death. Cancer is the second most common cause of death in the US and it is estimated that in 2015 more than 1.5 million new cases will be diagnosed and 589,430 Americans will die of cancer. With growing and ageing of the population these numbers are constantly growing and worldwide in 2030 about 21.7 million new cancer cases and 13 million cancer deaths are expected to occur (American Cancer Society, Cancer Facts and Figures, 2015).
On the current therapies the 5-years survival rate of all cancer patients is at about 68%, however, for particular cancer types it might be significantly lower, e.g. the 5-years survival rates of liver and lung cancer are 17%, of pancreatic cancer 7% and of glioblastoma less than 5% (American Cancer Society, Cancer Facts and Figures, 2015). These data strongly indicate that there is a need for new cancer therapeutics.
Gene expression controls the normal function, proliferation and differentiation of a cell. In normal cells gene expression is tightly regulated at multiple levels and steps, however, in cancer cells these mechanisms are often altered. Histone tails are well known protein-protein interaction domains which play a central role in gene expression regulation. They are subject to wide range of post-translational modification including methylation and acetylation. These modifications are reversible, i.e. specific “writer” and “eraser” enzymes exist which add or remove these marks. Ultimately, these marks are interpreted by “reader” proteins, which are known to translate these marks into gene expression changes.
Acetylation of histone tails is associated with active gene expression. Bromodomain, a small helical interacting module, is the best known protein domain which can specifically recognize and bind to the acetylated histone tails. Human genome encodes for 46 proteins contain altogether 61 diverse bromodomains (Filippakopoulos and Knapp, 2012, FEBS Let, 586: (17), 2692-2704). Bromodomain proteins recruit transcriptional machinery to acetylated chromatin sites and facilitate transcriptional activation. Bromodomain proteins are frequently implicated in cancer and the survival of different cancer types depend on their function (Muller et al., 2011, Epert Rev Mol Med, 13: e29; Shi J. et al., 2015, Nat Biotechnol, 33: (6), 661-667). Therefore recently several bromodomain inhibitors were developed to inhibit their binding to acetylated histone tails and to regulated gene expression. Some of these inhibitors have also entered clinical trials (Tanaka et al., 2015, Pharm Pat Anal, 4: (4), 261-284).
ATAD2, also known as ANCCA or PRO2000, is a bromodomain and AAA ATPase domain containing nuclear protein. ATAD2 was shown to function as a co-factor of oncogenic transcriptional factors such as MYC (Ciro et al., 2009, Cancer Res, 69: (21), 8491-8498), oestrogen receptor (ERα) (Zou et al., 2007, PNAS, 104: (46), 18067-18072), androgen receptor (AR) (Zou et al., 2009, Cancer Res, 69: (8) 3339-3346) and E2F (Revenko et al., 2010, Mol Cell Biol, 30: (22), 5260-5272) to activate the expression of their target genes involved in cell proliferation and survival. Such genes are different cyclins, cyclin-dependent kinases and kinesins. In normal tissues ATAD2 is expressed only in male germ cells, while in other normal tissues it is very low expressed and it could be detected only in dividing cells (Caron et al., 2010, Oncogene, 29: (37), 5171-5181). However, in large number of tumour types ATAD2 is frequently amplified and highly overexpressed, and its expression correlates with the advanced progression, metastasis and poor prognosis of breast cancer (Kalashnikova et al., 2010, Cancer Res, 70: (22), 9402-9412), endometrial cancer (Raeder et al., 2013, PlosOne, 8: (2), e54873), ovarian cancer (Wan et al., 2014, Asian Pac J Cancer Prev, 15: (6) 2777-2783), liver cancer (Wu et al., 2014, BMC Cancer, 14: (107), 1-11), cervical cancer (Zheng et al., 2015, Oncology Reports, 33: (5), 2337-2344) and lung cancer (Caron et al., 2010, Oncogene, 29: (37), 5171-5181). Until now ATAD2 was published to be overexpressed in breast cancer (Kalashnikova et al., 2010, Cancer Res, 70: (22), 9402-9412), endometrial cancer (Raeder et al., 2013, PlosOne, 8: (2), e54873), ovarian cancer (Wan et al., 2014, Asian Pac J Cancer Prev, 15: (6) 2777-2783), liver cancer (Wu et al., 2014, BMC Cancer, 14: (107), 1-11), colon cancer (Ciro et al., 2009, Cancer Res, 69: (21), 8491-8498), lung cancer (Fouer et al., 2012, Clin Cancer Res, 18: (20), 5606-5616), stomach cancer (Ciro et al., 2009, Cancer Res, 69: (21), 8491-8498), uterus cancer (Ciro et al., 2009, Cancer Res, 69: (21), 8491-8498), lymphoma (Ciro et al., 2009, Cancer Res, 69: (21), 8491-8498), cervical cancer (Zheng et al., 2015, Oncology Reports, 33: (5), 2337-2344), bladder cancer (Caron et al., 2010, Oncogene, 29: (37), 5171-5181), prostate cancer (Duan et al., 2013, Prostate, 73: (5), 455-466) and glioblastoma (Raeder et al., 2013, PlosOne, 8: (2), e54873). In normal breast tissues ATAD2 is barely detectable, while in tumour breast tissues ATAD2 expression was shown to increase with the grade and the proliferation state of the tumour (Kalashnikova et al., 2010, Cancer Res, 70: (22), 9402-9412). Moreover ATAD2 is one of the 70-genes signature predicting the disease outcome and one of the 76-gene signature that predict the disease outcome and the distant metastasis in breast cancer (Wang et al., 2005, Lancet, 365: (9460), 671-679). Down-regulation of ATAD2 by RNAi in cancer cells was shown to inhibit the proliferation and invasiveness of breast cancer cells (Kalashnikova et al., 2010, Cancer Res, 70: (22), 9402-9412; Revenko et al., 2010, Mol Cell Biol, 30: (22), 5260-5272), endometrial cancer cells (Raeder et al., 2013, PlosOne, 8: (2), e54873), ovarian cancer cells (Wan et al., 2014, Asian Pac J Cancer Prev, 15: (6) 2777-2783), liver cancer cells (Wu et al., 2014, BMC Cancer, 14: (107), 1-11), prostate cancer cells (Zou et al., 2009, Cancer Res, 69: (8) 3339-3346), cervical cancer cells (Zheng et al., 2015, Oncology Reports, 33: (5), 2337-2344), osteosarcoma (Ciro et al., 2009, Cancer Res, 69: (21), 8491-8498) and to promote apoptotic cancer cell death (Caron et al., 2010, Oncogene, 29: (37), 5171-5181).
Bromodomain of ATAD2 was found to bind different acetylation marks including H3K14ac (Revenko et al., 2010, Mol Cell Biol, 30: (22), 5260-5272) and H4K5Ac (Caron et al., 2010, Oncogene, 29: (37), 5171-5181) A rescue experiment by Revenko and colleagues demonstrated that mutagenesis of ATAD2 bromodomain inactivated ATAD2 function, which could not substitute for the wild-type ATAD2 in gene expression and survival of cancer cells. This suggest an essential function of the bromodomain of ATAD2 in cancer cells (Revenko et al., 2010, Mol Cell Biol, 30: (22), 5260-5272). Therefore potent and selective small molecular weight inhibitory compounds targeting the bromodomain function of ATAD2 might be useful for treatment of cancer types where ATAD2 is implicated in.
From WO2012/055880 the use of ATAD2 inhibitors for the treatment of autoimmune and inflammatory diseases is known.
The treatment of cancer is still a remaining problem. Thus there is the need for further provision of effective anti-cancer agents. The present invention identifies compounds which surprisingly are ATAD2 bromodomain inhibitors for which data are provided in the experimental section and which may thus be suitable for the treatment or prophylaxis of cancer.
In a first aspect, the present invention relates to compounds of general formula (I)
in which    R1 represents a benzyl group wherein the α-position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group,    R2 represents a C1-6-alkyl group,            a C1-6-hydroxyalkyl group,        a —C1-3-alkylen-O—(C1-6-alkyl) group,        a —C1-6-aminoalkyl group,        a —C1-3-alkylen-N—(C1-6-alkyl)2 group,        a —C1-3-alkylen-NH—(C1-6-alkyl) group,        a —C1-3-alkylen-NH—(C1-4-alkyl)-OH group,        a —C1-3-alkylen-NH—(C3-7-cycloalkyl)-NH2 group,        a —C1-3-alkylen-NH—C1-4-alkylen-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a —C1-3-alkylen-NH-heterocycloalkyl group which is optionally substituted independently from each occurrence one or more times with C1-4-alkyl, halogen, benzyl, C(O)R7,        a —C1-3-alkylen-NH—(C1-3-alkylen)-phenyl group        a —C1-3-alkylen-NH—C(O)(C1-4-alkyl) group,        a —C1-3-alkylen-NH—C(O)—C1-4-alkylen-heterocycloalkyl group,        a —C1-3-alkylen-NH—C1-3-alkylen-C(O)-heterocycloalkyl group,        a —C1-3-alkylen-NH—C(O)-heterocycloalkyl group,        a —C1-3-alkylen-NH—S(O)2—(C1-4-alkyl) group,        a —C1-3-alkylen-(4-cyano-phenyl) group,        a —C1-3-alkylen-C(O)—NH—(C1-6-alkyl) group,        a —C1-3-alkylen-C(O)—NH—(C1-4-alkyl)-OH group        a —C1-3-alkylen-C(O)—NR8R9 group,        a —C1-3-alkylen-C(O)—R7 group,        a —C1-3-alkylen-C(O)-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a —C1-3-alkylen-heterocycloalkyl group which is optionally one or more times substituted with C1-3-alkyl,        a C(O)R7 group,        a —C(O)—NR8R9 group,        a —C(O)—NH—(C3-7-cycloalkyl)-NH2 group,        a —C(O)—NH-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a heteroaryl group,            R3 a —C1-3-alkylen-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C1-3-alkyl, C1-3-alkoxy, amino, C(O)R7, C(O)NR8R9,            a —C1-4-alkylen-heteroaryl group, or        R2 and R3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom of absolute configuration R        
    R4 represents a hydrogen atom, a methyl group, a chlorine atom,    R5 represents a hydrogen atom or a halogen atom    R6 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-3 alkoxy group, or a cyano group,    R7 represents a —O—C1-4-alkyl group,    R8, R9, represents, independently for each occurrence, a hydrogen atom or a C1-4-alkyl group,or the salts thereof, the solvates thereof or the solvates of the salts thereof,with the proviso that the following compounds    2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamideare excluded.
In a second aspect, the present invention relates to compounds of general formula (I) in which    R1 represents a benzyl group wherein the α-position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group,    R2 represents a C1-6-alkyl group,            a C1-6-hydroxyalkyl group,        a —C1-3-alkylen-O—(C1-6-alkyl) group,        a —C1-6-aminoalkyl group,        a —C1-3-alkylen-N—(C1-6-alkyl)2 group,        a —C1-3-alkylen-NH—(C1-6-alkyl) group,        a —C1-3-alkylen-NH—(C1-4-alkyl)-OH group,        a —C1-3-alkylen-NH—(C3-7-cycloalkyl)-NH2 group,        a —C1-3-alkylen-NH—C1-4-alkylen-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a —C1-3-alkylen-NH-heterocycloalkyl group which is optionally substituted independently from each occurrence one or more times with C1-4-alkyl, halogen, benzyl, C(O)R7,        a —C1-3-alkylen-NH—(C1-3-alkylen)-phenyl group,        a —C1-3-alkylen-NH—C(O)(C1-4-alkyl) group,        a —C1-3-alkylen-NH—C(O)—C1-4-alkylen-heterocycloalkyl group,        a —C1-3-alkylen-NH—C1-3-alkylen-C(O)-heterocycloalkyl group,        a —C1-3-alkylen-NH—C(O)-heterocycloalkyl group,        a —C1-3-alkylen-NH—S(O)2—(C1-4-alkyl) group,        a —C1-3-alkylen-(4-cyano-phenyl) group,        a —C1-3-alkylen-C(O)—NH—(C1-6-alkyl) group,        a —C1-3-alkylen-C(O)—NH—(C1-4-alkyl)-OH group,        a —C1-3-alkylen-C(O)—NR8R9 group,        a —C1-3-alkylen-C(O)—R7 group,        a —C1-3-alkylen-C(O)-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a —C1-3-alkylen-heterocycloalkyl group which is optionally one or more times substituted with C1-3-alkyl,        a C(O)R7 group,        a —C(O)—NR8R9 group,        a —C(O)—NH—(C3-7-cycloalkyl)-NH2 group        a —C(O)—NH-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a heteroaryl group,            R3 a —C1-3-alkylen-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C1-3-alkyl, C1-3-alkoxy, amino, C(O)R7, C(O)NR8R9,            a —C1-4-alkylen-heteroaryl group or        R2 and R3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom of absolute configuration R        
    R4 represents a chlorine atom,    R5 represents a hydrogen atom    R6 represents a hydrogen atom,    R7 represents a —O—C1-4-alkyl group    R8, R9, represents, independently for each occurrence, a hydrogen atom or a C1-4-alkyl group,or the salts thereof, the solvates thereof or the solvates of the salts thereof,with the proviso that the following compounds    2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamideare excluded.
In a further embodiment the present invention relates to compounds of general formula (I)
in which
    R1 represents a benzyl group wherein the α-position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group,    R2 represents a C1-3-alkyl group,            a C1-3-hydroxyalkyl group,        a —C1-3-alkylen-O—(C1-3-alkyl) group,        a —C1-3-aminoalkyl group,        a —C1-3-alkylen-N—(C1-3-alkyl)2 group,        a —C1-3-alkylen-NH—(C1-3-alkyl) group,        a —C1-3-alkylen-NH—(C1-3-alkyl)-OH group,        a —C1-3-alkylen-NH—(C5-6-cycloalkyl)-NH2 group,        a —C1-3-alkylen-NH—C1-3-alkylen-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a —C1-3-alkylen-NH-heterocycloalkyl group which is optionally substituted independently from each occurrence one or more times with C1-4-alkyl, halogen, benzyl, C(O)R7,        a —C1-3-alkylen-NH—(C1-3-alkylen)-phenyl group,        a —C1-3-alkylen-NH—C(O)(C1-3-alkyl) group,        a —C1-3-alkylen-NH—C(O)—C1-3-alkylen-heterocycloalkyl group,        a —C1-3-alkylen-NH—C1-3-alkylen-C(O)-heterocycloalkyl group,        a —C1-3-alkylen-NH—C(O)-heterocycloalkyl group,        a —C1-3-alkylen-NH—S(O)2—(C1-3-alkyl) group,        a —C1-3-alkylen-(4-cyano-phenyl) group,        a —C1-3-alkylen-C(O)—NH—(C1-3-alkyl) group,        a —C1-3-alkylen-C(O)—NH—(C1-3-alkyl)-OH group        a —C1-3-alkylen-C(O)—NR8R9 group,        a —C1-3-alkylen-C(O)—R7 group,        a —C1-3-alkylen-C(O)-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a —C1-3-alkylen-heterocycloalkyl group which is optionally one or more times substituted with C1-3-alkyl,        a C(O)R7 group,        a —C(O)—NR8R9 group,        a —C(O)—NH—(C5-6-cycloalkylen)-NH2 group,        a —C(O)—NH-heterocycloalkyl group which is optionally substituted with C1-3-alkyl,        a heteroaryl group,            R3 a —C1-3-alkylen-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C1-3-alkyl, C1-3-alkoxy, amino, C(O)R7, C(O)NR8R9,            a —C1-4-alkylen-heteroaryl group, or        R2 and R3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom        
    R4 represents a hydrogen atom, a methyl group, a chlorine atom,    R5 represents a hydrogen atom or a halogen atom    R6 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-3 alkoxy group, or a cyano group,    R7 represents a —O—C1-4-alkyl group    R8, R9, represents, independently for each occurrence, a hydrogen atom or a C1-4-alkyl group,or the salts thereof, the solvates thereof or the solvates of the salts thereof,
with the proviso that the following compounds    2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamideare excluded.
In another embodiment, the present invention relates to compounds of general formula (I
in which
    R1 represents a benzyl group wherein the α-position is substituted by one methyl group of R configuration or two methyl groups, and the 4-position may be substituted by a methyl group, a halogen atom, a 4-trifluoromethyl group,    R2 represents a methyl group,            a hydroxymethyl group,        —(CH2)2OH,        —C(OH)(CH3)2,        —CH(OH)CH3,        —C(OH)(CH3)2,        —CH(OH)—CH2—CH(CH3)2,        —CH2—O—CH3,        —CH2—NH2,        —CH2—N(CH3)2,        —(CH2)2—NH—CH(CH3)2,        —CH2—NH—CH2—CH(CH3)2,        —CH2—NH—(CH2)2—OH,        —CH2—NH-(1,4-cyclohexylen)-NH2,        —CH2—NH—(CH2)2-piperidine-4-yl,        —(CH2)2—NH—CH2-(1-methyl-piperidine-4-yl),        —CH2—NH—CH2-(3-azabicyclo[3.1.0]hex-6-yl),        —CH2—NH-(1-ethyl-piperidine-4-yl),        —CH2—NH-(1-isobutyl-piperidine-4-yl),        —CH2—NH-(1-phenylmethyl-piperidine-4-yl),        —CH2—NH-(1-tert.butoxycarbonyl-piperidine-4-yl),        —CH2—NH-2,2-dimethyl-piperidine-4yl),        —(CH2)2—NH-(1-methyl-pyrrolidin-3-yl),        —CH2—NH-(piperidin-4-yl),        —CH2—NH-(1-methyl-piperidin-4-yl),        —CH2—NH-(2-methyl-propyl-piperidin-3-yl),        —CH2—NH-(3-fluoropiperidin-4-yl),        —CH2—NH—CH2-phenyl,        —CH2—NH—C(O)—CH3,        —CH2—NH—C(O)—CH2-piperidine-4-yl,        —CH2—NH—CH2—C(O)-piperazine-1-yl,        —CH2—NH—C(O)-piperidine-4-yl, —CH2—NH—S(O)2—CH3,        —CH2-(4-cyano-phenyl),        —CH2—C(O)—NH—CH3,        —CH2—C(O)—NH—(CH3)2,        —CH2—C(O)—NH—CH(CH3)2,        —CH2—C(O)—NH—(CH2)2—OH,        —CH2—C(O)—NH—(CH2)3—OH,        —CH2—C(O)—NH2,        —CH2—C(O)—N(CH3)2,        —CH2—C(O)—NH—CH3,        —CH2—C(O)—OCH3,        —CH2—C(O)-(morpholine-4-yl),        —CH2—C(O)-(4-methyl-piperazine-1-yl),        —CH2—C(O)—(N-pyrrolidine),        —(CH2)2-(3-methylpiperazine-1-yl),        —CH2-(4-methyl-piperazine-1-yl),        —(CH2)2-(4-methyl-piperazine-1-yl),        —CH2-(morpholine-4-yl),        —(CH2)2-(morpholine-4-yl),        —(CH2)2-(2,4-dimethylpiperazine-1-yl),        —(CH2)2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl),        —CH2—(N-pyrrolidine),        —C(O)OCH3,        —C(O)—NH2,        —C(O)NH-(4-amino-cyclohexylen),        —C(O)—NH-(1-methyl-piperidine-4-yl),        1H-1,2,4-triazol-5-yl,        1H-imidazol-2-yl,            R3 a —CH2-phenyl group which is independently from each occurrence optionally substituted 1 to 3 times with a substituent selected from the group cyano, halogen, C1-3-alkyl, C1-3-alkoxy, amino, C(O)R7, C(O)NR8R9,            —CH2-pyridine-4-yl, or R2 and R3 together with the carbon atom to which they are attached form the following 6-membered ring whereby the star * indicates the carbon atoms which are attached to said carbon atom        
    R4 represents a hydrogen atom, a methyl group, a chlorine atom,    R5 represents a hydrogen atom or a fluorine atom    R6 represents a hydrogen atom, a chlorine atom, a hydroxy group, a C1-3 alkoxy group, or a cyano group,    R7 represents a methoxy group    R8, R9, represents, independently for each occurrence, a hydrogen atom or a methyl group,or the salts thereof, the solvates thereof or the solvates of the salts thereof,
with the proviso that the following compounds    2-Chlor-N-[(2R)-1-(4-cyanphenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-fluorophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-fluorophenyl)ethyl]amino}methyl)-2-furyl]benzamideare excluded.
In one aspect of the invention compounds of formula (I) as described above are selected from the group consisting of:    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(dimethylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    Nα-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}-4-cyano-D-phenylalaninamide,    N-[(2R)-4-amino-1-(4-cyanophenyl)-4-oxobutan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)-2-furyl]benzamide,    Nα-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzoyl}-4-cyano-N-methyl-D-phenylalaninamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(isopropylamino)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(2-hydroxyethyl)amino]-4-oxobutan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(3-hydroxypropyl)amino]-4-oxobutan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-oxo-4-(pyrrolidin-1-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(morpholin-4-yl)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(4-methylpiperazin-1-yl)-4-oxobutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxy-3-methylbutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-hydroxybutan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-methoxypropan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    methyl N-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzoyl}-4-cyano-D-phenylalaninate,    2-chloro-N-[(2R,3R)-1-(4-cyanophenyl)-3-hydroxybutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R,3R)-1-(4-cyanophenyl)-3-hydroxybutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-hydroxy-3-(4-iodophenyl)propan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(1S)-2-(4-cyanophenyl)-1-(1H-imidazol-2-yl)ethyl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(1R)-2-(4-cyanophenyl)-1-(1H-1,2,4-triazol-5-yl)ethyl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(4-methylpiperazin-1-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(morpholin-4-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(2-hydroxyethyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(dimethylamino)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(4-methylpiperazin-1-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(propan-2-ylamino)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(3R)-3-methylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(3S)-3-methylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(morpholin-4-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    Nα-{2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzoyl}-4-cyano-N-(1-methylpiperidin-4-yl)-D-phenylalaninamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(2S)-2,4-dimethylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-4-[(2R)-2,4-dimethylpiperazin-1-yl]butan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-{[(1-methylpiperidin-4-yl)methyl]amino}butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-{[(3R)-1-methylpyrrolidin-3-yl]amino}butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-{[(3S)-1-methylpyrrolidin-3-yl]amino}butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)butan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyano-3-methylphenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyano-5-fluoro-2-methylphenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyano-2-methoxyphenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    N-[(2R)-1-(3-amino-4-cyanophenyl)-3-hydroxypropan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-(2-amino-4-cyanophenyl)-3-hydroxypropan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2S)-1-(4-cyanophenyl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)-ethyl]amino}methyl)-2-furyl]benzamide,    N-[(2R)-1-(acetylamino)-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(3-cyanophenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R,3R)-1-(4-cyanophenyl)-3-hydroxy-5-methylhexan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R,3S)-1-(4-cyanophenyl)-3-hydroxy-5-methylhexan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-hydroxy-3-(pyridin-4-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-(4-carbamoylphenyl)-3-hydroxypropan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(pyrrolidin-1-yl)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    methyl (3R)-3-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzoyl}amino)-4-(4-cyanophenyl)butanoate,    methyl 4-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-furan-2-yl]benzoyl}amino)-3-hydroxypropyl]benzoate,    N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(methylsulfonyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[2-oxo-2-(piperazin-1-yl)ethyl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzoyl}amino)-3-(4-cyanophenyl)propyl]piperidine-4-carboxamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(piperidin-4-ylacetyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(1-methylpiperidin-4-yl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    N-[(2R)-1-[(1-benzylpiperidin-4-yl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-(benzylamino)-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(2-methylpropyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(1-ethylpiperidin-4-yl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[1-(2-methylpropyl)piperidin-4-yl]amino}-propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    tert-butyl 4-{[(2R)-2-({2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-furan-2-yl]benzoyl}amino)-3-(4-cyanophenyl)propyl]amino}piperidine-1-carboxylate,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[(3S)-1-methylpiperidin-3-yl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-{[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-ylmethyl]amino}-3-(4-cyanophenyl)-propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-(piperidin-4-ylamino)propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[(4R)-2,2-dimethylpiperidin-4-yl]amino}-propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-{(2R)-1-(4-cyanophenyl)-3-[(piperidin-4-ylmethyl)amino]propan-2-yl}-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[2-(piperidin-4-yl)ethyl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}propan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-{5-[({2-[4-(trifluoro-methyl)phenyl]propan-2-yl}amino)methyl]furan-2-yl}benzamide,    N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-5-{5-[({(1R)-1-[4-(trifluoro-methyl)phenyl]ethyl}amino)methyl]furan-2-yl}benzamide,    2-chloro-N-[(3R,4R)-4-(4-cyanophenyl)piperidin-3-yl]-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-3-fluoro-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2,4-dichloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    4-cyano-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-3-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-methoxy-2-methyl-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide,    2-chloro-N-[(2R)-1-(4-cyano-3-methylphenyl)-3-hydroxypropan-2-yl]-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-amino-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-amino-3-(4-cyano-3-methylphenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-(trans-4-aminocyclohexyl)-Nα-{2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methyl-phenyl)ethyl]amino}methyl) furan-2-yl]benzoyl}-4-cyano-D-phenylalaninamide,    N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyanophenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide,    N-[(2R)-1-[(cis-4-aminocyclohexyl)amino]-3-(4-cyano-3-methylphenyl)propan-2-yl]-2-chloro-4-methoxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]-benzamide,    2-chloro-5-[5-({[(1R)-1-(4-chlorophenyl)ethyl]amino}methyl)furan-2-yl]-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]benzamide, and    2-chloro-N-[(2R)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]-4-hydroxy-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl) furan-2-yl]benzamide.    4-cyano-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-3-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide    2-chloro-N-[(2R)-4-(methylamino)-4-oxo-1-phenylbutan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)furan-2-yl]benzamide    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-(5-{[(2-phenylpropan-2-yl)amino]methyl}furan-2-yl)benzamide    2-chloro-N-[(2R)-1-(4-cyanophenyl)-4-(methylamino)-4-oxobutan-2-yl]-5-[5-({[2-(4-methylphenyl)propan-2-yl]amino}methyl)-2-furyl]benzamide    Nα-{2-chloro-5-[5-({[2-(4-chlorophenyl)propan-2-yl]amino}methyl)-2-furyl]benzoyl}-4-cyano-D-phenylalaninamide    2-chloro-N-[(2R)-1-hydroxy-3-phenylpropan-2-yl]-5-[5-({[(1R)-1-(4-methylphenyl)ethyl]amino}methyl)-2-furyl]benzamide
In accordance with a further aspect, the present invention provides compounds of general formula (I), as described supra, or stereoisomers, tautomers, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular hyperproliferative disorders, more particularly cancer disorders.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
The term “pharmaceutically acceptable salt” refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds of the invention. However, salts which are also encompassed are salts which are not themselves suitable for pharmaceutical applications, but may be used for example for isolating or purifying the compounds according to the invention.
A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl) ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.
Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or “x HCl”, “x CF3COOH”, “x Na+”, for example, mean a salt form, the stoichiometry of which salt form not being specified.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition.
Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Where the compounds according to the invention can occur in tautomeric forms, the present invention includes all the tautomeric forms.
It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
The term “Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The term “Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.
Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 125I, 129I and 131I, respectively.
With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3H or 14C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18F or 11C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, Mass., USA; and CombiPhos Catalysts, Inc., Princeton, N.J., USA.
The term “deuterium-containing compound of general formula (I)” is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased.
The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound's pharmacokinetic/pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/112363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch./Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
In another embodiment the present invention concerns a deuterium-containing compound of general formula (I) having 1, 2, 3 or 4 deuterium atoms, particularly with 1, 2 or 3 deuterium atoms.